Overall: Summary/Abstract: The University of Pittsburgh Alzheimer?s Disease Research Center (PITT- ADRC) has shown a clear scientific evolution over the past three decades. Since our inception, we have advanced the areas of AD neuropsychiatry, genetics, natural history of AD, validation of clinical criteria, and clinico-pathological correlations, and have pioneered the development of PET amyloid tracers, which have transformed AD research. We have used a multidisciplinary approach to better understand the transition from normal cognition to dementia, have explored the biology of more aggressive forms of AD characterized by psychosis, and have made and contributed to new insights in genetics. This solid scientific background and investment in junior investigators has allowed the PITT-ADRC to develop areas of excellence, which form the foundation of our Center going forward. These are reflected in the Center?s cores, and most notably in the large number of studies we support in these areas in Pittsburgh and at national and international level. The PITT-ADRC is committed to remain at the forefront of the scientific efforts to understand the pathological processes involved in the etiology of AD. Along with the high level of research conducted by the PITT-ADRC, we are also dedicated to developing strong training programs to promote the careers of young investigators, consolidate the career of midlevel investigators, and to create strong ties with the community through educational and support programs. The PITT-ADRC is highly committed to leverage the strengths of the network of Centers to provide large numbers of samples and standardized clinical data collection from our participants. The PITT-ADRC has designed novel methodology that improves the accessibility of its database to local and national researchers, and it has been a key player in multiple studies that advanced the understanding of AD pathology and its possible implications for the development of novel treatments and other symptoms. Therefore, we provide an excellent environment that enhances cutting-edge research by bringing together a multidisciplinary team of investigators to study AD and other dementias, and to improve health care delivery. The methodology proposed in this application will lead us to the creation of a unique and well-characterized cohort of patients and normal control subjects assessed with state of the art clinical and biomarker methods. This will allow us to test multiple scientific hypotheses and to examine the short- and long-term public health outcomes of the pathophysiology of cognitive disorders in the adult. We believe that the PITT -ADRC will be at the center of the new era of AD research that will require a wealth of clinical and biological data, highly sophisticated biomarker methodologies, close inter-relationship among centers and institutions, creation and optimization of human resources, and enhanced communication with patients and families.